Triazolo [4,3-c]pyrimidines substituted by nitrogen-containing heterocyclic rings

ABSTRACT

1,2,4-Triazolo[4,3-c]pyrimidines substituted at the 5 or 7 position through a nitrogen atom which is part of a heterocyclic ring have been found to have potent bronchodilator activity and to be useful synthetic intermediates in the preparation of 1,2,4-triazolo[1,5-c]-pyrimidines. Methods for inducing bronchodilation, pharmaceutical compositions, and synthetic processes and intermediates are also described.

TECHNICAL FIELD

The present invention relates to triazolo[4,3-c]pyrimidines, and morespecifically to 1,2,4-triazolo[4,3-c]pyrimidines. The pharmacologicaluse of the compounds as bronchodilators, pharmaceutical compositionscomprising the compounds, and intermediates useful for preparing thecompounds are also within the scope of the invention.

BACKGROUND OF THE INVENTION

Some 1,2,4-triazolo[4,3-c]pyrimidines are known to the art. Certain3-amino-1,2,4-triazolo[4,3-c]pyrimidines are disclosed in the patentsdiscussed below:

United Kingdom Pat. No. 859,287 discloses what were believed to be thecompounds 3-amino-7-methyl-5-methylthio-1,2,4-triazolo[4,3-c]pyrimidineand 3-amino-7-chloro-5-methyl-1,2,4-triazolo[4,3-c]pyrimidine.

United Kingdom Pat. No. 898,408 discloses3-amino-1,2,4-triazolo[4,3-c]pyrimidines which are substituted on thepyrimidine ring at the 5-position by an alkyl, alkylthio, or aminosubstituent, at the 7-position by an alkyl, halogen-substituted alkyl orhalogen substituent, and at the 8-position by hydrogen or an alkyl oralkenyl substituent. These compounds are said to be bronchodilators.

The following related articles disclose the synthesis of certain1,2,4-triazolo[4,3-c]pyrimidines as intermediates in the preparation of1,2,4-triazolo[1,5-c]pyrimidines and as potential bronchodilators.

G. W. Miller et al., J. Chem. Soc., 1963, 5642, discloses1,2,4-triazolo[4,3-c]pyrimidines which are substituted at the 3-positionby amino or imino substituents, and on the pyrimidine ring by alkylsubstituents or alkyl and alkenyl substituents.

G. W. Miller et al., J. Chem. Soc., 1963, 3357, discloses the compound3-hydroxy-7-methyl-5-n-propyl-1,2,4-triazolo[4,3-c]pyrimidine.

W. Broadbent et al., J. Chem. Soc., 1963, 3369, discloses the compound3-mercapto-7-methyl-5-n-propyl-1,2,4-triazolo[4,3-c]pyrimidine.

Still other 3-amino-1,2,4-triazolo[4,3-c]pyrimidines are disclosed inthe following articles and patent:

Shiho et al., Yakagaku Zasshi, 1956, 76, 804, discloses1,2,4-triazolo[4,3-c]pyrimidines which are substituted at the 3-positionby alkyl or phenyl substituents, and on the pyrimidine ring by bothmethyl and methoxy substituents.

Temple et al., J. Org. Chem., 1968, 33, 530, discloses the compound8-amino-7-chloro-5-triazolo-[4,3-c]pyrimidine-3(2H)-one.

D. J. Brown et al., Aust. J. Chem., 1978, 31, 2505, discloses1,2,4-triazolo[4,3-c]pyrimidines which are substituted at the 3-positionby hydrogen or alkyl substituents, and on the pyrimidine ring byhydrogen and/or alkyl substituents.

D. J. Brown et al., Aust. J. Chem. 1979, 32, 1585, discloses1,2,4-triazolo[4,3-c]pyrimidines which are substituted at the 3-positionby hydrogen or an alkyl substituent, and on the pyrimidine ring at the5-position by a halogen, hydrazino, methylthio or methyl substituent,and at the 7-position by a methyl substituent.

U.S. Pat. No. 4,269,980 discloses 5-, 7- and 8-(optionallysubstituted-phenyl)-1,2,4-triazolo[4,3-c]-pyrimidines. These compoundsmay be substituted at the 3-position by hydrogen or an alkyl substituentand are anxiolytic agents.

The triazolo[4,3-c]pyrimidines of the present invention differ from theprior art compounds in that the compounds of the present inventioncontain a heterocyclic substituent on the pyrimidine ring. Theheterocyclic substituent is bonded to the pyrimidine nucleus in the 5 or7 position through a nitrogen atom which is part of the heterocyclicgroup.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to 1,2,4-triazolo-[4,3-c]pyrimidines whichare bronchodilators. The invention also relates to a method for inducingbronchodilation in a mammal using a 1,2,4-triazolo[4,3-c]pyrimidine ofthe invention, and to pharmaceutical compositions comprising aneffective amount of a 1,2,4-triazolo[4,3-c]pyrimidine of the inventionand a pharmaceutically acceptable carrier. The invention also relates tosynthetic processes and intermediates useful for preparing the1,2,4-triazolo-[4,3-c]pyrimidines of the invention.

Specifically, the present invention relates to compounds of the formulaI ##STR1## wherein R₃ is hydrogen or lower alkyl; one of of R₅ and R₇ isthe heterocyclic substituent ##STR2## wherein X is oxygen, sulfur,sulfinyl, sulfonyl, methylene (--CH₂ --), imido (--NH--) or N-loweralkylimido ##STR3## when R₅ is the above heterocyclic substituent, R₇ ishydrogen or lower alkyl; when R₇ is the above heterocyclic substituent,R₅ is hydrogen, lower alkylthio, phenyl, or lower alkyl; and R₈ ishydrogen, phenyl or lower alkyl; and pharmaceutically acceptable saltsthereof.

The present invention also relates to compounds of the following formula##STR4## wherein R₅ is hydrogen, lower alkyl, phenyl or lower alkylthio;R₈ is hydrogen, phenyl or lower alkyl; and X is oxygen, sulfur,sulfonyl, methylene, imido or N-lower alkylimido. These compounds areuseful intermediates in the preparation of compounds of Formula I.

The present invention further relates to compounds of the followingformula ##STR5## wherein R₅ is hydrogen, lower alkyl, phenyl or loweralkylthio; R₈ is hydrogen, phenyl or lower alkyl; and X is oxygen,sulfur, sulfonyl, methylene, imido or N-lower alkylimido. Thesecompounds are also useful intermediates in the preparation of compoundsof Formula I.

"Lower alkyl" as used in the instant specification and claims designatesstraight or branched-chain alkyl groups containing one to about 4 carbonatoms. Preferred lower alkyl groups are methyl, ethyl and propyl.

The presently preferred compounds of Formula I are those wherein X issulfur or oxygen and R₈ is hydrogen. These compounds are preferredbecause of their generally higher activity in protecting againsthistamine-induced contraction of isolated guinea pig tracheal tissue.This assay is discussed in greater detail below.

Specific examples of preferred compounds of Formula I which are activein the aforementioned assay at concentrations of 10 ug per ml of lowerare:

3,5-bis(n-propyl)-7-(4-thiomorpholino)-1,2,4-triazolo[4,3-c]-pyrimidine,

5-ethyl-3-methyl-7-(4-thiomorpholino)-1,2,4-triazolo[4,3-c]-pyrimidine,

3-methyl-5-methylthio-8-phenyl-7-(4-thiomorpholino)-1,2,4-triazolo[1,5-c]pyrimidine,

5-ethyl-3-isopropyl-7-(4-thiomorpholino)-1,2,4-triazolo-[4,3-c]pyrimidine,

3-ethyl-5-methyl-7-(4-thiomorpholino)-1,2,4-triazolo-[4,3-c]pyrimidine,

3,5-bis(n-propyl)-7-(4-morpholino)-1,2,4-triazolo[4,3-c]-pyrimidine,

3,5-diethyl-7-(1-piperidino)-1,2,4-triazolo[4,3-c]pyrimidine,

2-ethyl-7-(4-morpholino)-5-n-propyl-1,2,4-triazolo[1,5-c]-pyrimidine,

7-(4-morpholino)-5-methylthio-1,2,4-triazolo[4,3-c]pyrimidine,

3-ethyl-5-n-propyl-7-(4-thiomorpholino)-1,2,4-triazolo-[4,3-c]pyrimidine,

7-(4-methyl-1-piperazino)-5-(n-propyl)-1,2,4-triazolo[4,3-c]-pyrimidine,

5-n-propyl-7-(4-thiomorpholino)-1,2,4-triazolo[4,3-c]-pyrimidine,

5-ethyl-7-(4-morpholino)-1,2,4-triazolo[4,3-c]pyrimidine,

5-ethyl-3-methyl-7-(4-morpholino)-1,2,4-triazolo[4,3-c]-pyrimidine,

3,5-diethyl-7-(4-thiomorpholino)-1,2,4-triazolo[4,3-c]-pyrimidine.

The bronchodilator activity of compounds of Formula I was assessed bythe measurement of effects on isolated tracheal spirals. This is awell-known and conventional test method. The bronchodilator activity wasdetermined as follows: Female guinea pigs were sacrificed and eachtrachea removed and cut into a spiral strip. This strip was mounted in aconstant temperature (37° C.) muscle bath having a volume ofapproximately 15 ml. The bathing medium was Krebs-Henseleit solution.Movement of the tracheal strip was measured by means of an isometrictransducer connected to an electric recorder. The bath was aerated witha mixture of 95% carbon dioxide and 5% oxygen. Contractions were inducedin the strips by the addition of a suitable amount of histamine,acetylcholine or barium chloride. The amount of a given compound ofFormula I (measured in microgram/ml) required to provide greater than75% relaxation of the drug induced contraction is considered aneffective concentration. For comparison, a well known standardbronchodilator, aminophylline, requires concentrations of 50microgram/ml versus histamine, 100 microgram/ml versus acetylcholine and10 microgram/ml versus barium chloride to provide greater than 75%relaxation.

Compounds of Formula I which were most active in the in vitro test,including most of those listed above as preferred compounds, were testedin vivo for oral activity in the guinea pig in the so-called histamineaerosol method described in U.S. Pat. No. 3,248,292. This test wasmodified slightly in that a 0.1% aqueous solution of histamine was usedas the agent for inducing bronchial constriction. Oral doses weremeasured in mg/kg of body weight of the guinea pig.

Some of the compounds of Formula I were also found to have activity asmucolytics in an in vitro test for mucus production in which rats areorally dosed with compound prior to sacrifice, and the trachea isisolated and incubated with radiolabelled glucosamine. The effect ofcompounds of the invention on the incorporation of glucosamine intoextracellular mucus is determined. An active compound such as5-methyl-7-thiomorpholino-1,2,4-triazolo[4,3-c]pyrimidine of theinvention reduces incorporation of glucosamine.

Compounds of Formula I may be administered to mammals in order to obtainbronchodilation. The compounds may be administered orally, parenterallyor by inhalation. Preferably, they are administered orally in the formof tablets or capsules. The usual effective human dose will be 0.1 to 50mg/kg of body weight.

Salts of compounds of Formula I are generally prepared by reaction withan equimolar amount of a relatively strong acid, preferably an organicacid such as hydrochloric, sulfuric or phosphoric acid, in a polarsolvent. Isolation of the salt is facilitated by the addition of asolvent in which the salt is insoluble, an example of such a solventbeing diethyl ether.

Compounds of Formula I, either as free bases or in the form of apharmaceutically acceptable acid-addition salt, can be combined withconventional pharmaceutical diluents and carriers to form such dosageforms at tablets, capsules, suspensions, solutions, suppositories andthe like.

The pharmaceutical carrier employed may be, for example, either a solidor liquid. Examples of solid carriers are lactose, terra alba, sucrose,talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid,and the like. Liquid carriers included syrup, peanut oil, olive oil,water and the like. Similarly, the carrier or diluent can incude anytime delay material well known to the art, such as glyceryl monostearateor glyceryl distearate, these being employed alone or in combinationwith, for example, a wax.

Compounds of Formula I may be prepared by several synthetic routes. Onesuch route is that shown in Scheme I below. This route is useful inpreparing compounds wherein R₅ is hydrogen, lower alkyl, lower alkylthioor phenyl; R₇ is ##STR6## wherein X is as defined previously; and R₃ andR₈ are as defined previously. Each "alk" appearing in Scheme I isindependently lower alkyl. ##STR7##

The reactions of steps (1), (2) and (3) have previously been reportedfor the preparation of compounds wherein R₅ is hydrogen, methyl or ethyland R₈ is hydrogen or methyl. Thus, most of the compounds of formulasIV, V and VI are known. Heterocyclic compounds of formulas VII and VIIIare novel. The known methods were used to carry out the reactions ofsteps (1), (2) and (3). Specifically, steps (1) and (2) were carried outas described in H. R. Henze et al., J. Org. Chem., 1952, 17, 1320 and H.R. Henze et al., J. Org. Chem., 1953, 18, 653, and step 3 was carriedout as described in J. Chesterfield et al., J. Chem. Soc., 1955, 3478.Example 1 hereinbelow details these steps.

Step (4) is carried out by reacting the optionally substituted4-chloro-6-hydrazinopyrimidine of Formula VI with a heterocyclic amineof the formula VIA. The reactants are heated together without solvent oroptionally (and preferably) in any solvent which does not participate inthe reaction such as water. Two equivalents of the heterocyclic amineare preferably used. Alternatively, one equivalent of the heterocyclicamine may be replaced by an inorganic base to neutralize the hydrogenchloride, but lower yields are generally obtained. The reaction mixtureis heated at a temperature up to or at its reflux temperature. Atemperature is chosen which provides an adequate reaction rate. Whenwater is used as the solvent, the temperature is generally in the rangeof 80° to 110° C. Good yields of the desired products are isolated byconventional methods such as filtration, extraction or chromatography.The novel intermediate of Formula VIII, which may also be prepared bysteps (5) and (6) discussed below, are solids whose structuralassignments are confirmed by infrared and nuclear magnetic resonancespectral analyses.

Step (5) is carried out by reacting the optionally substituted4,6-dichloropyrimidines of Formula V with heterocyclic amines of theformula VIA. The reaction is carried out by heating the reactantswithout solvent or preferably in any solvent which does not participatein the reaction. Two equivalents of the heterocyclic amine arepreferably used, one to react with the chloropyrimidine and the other toneutralize the hydrogen chloride by-product. Alternatively, an inorganicbase can be used to neutralize the hydrogen chloride by-product, butlower yields of the desired product are generally obtained. Heating isat a temperature up to and including the reflux temperature of themixture. A temperature is chosen which provides an adequate reactionrate. If water is used as a solvent, the mixture is generally heated atits reflux temperature. Good yields of the desired product are isolatedby conventional methods such as filtration, extraction orchromatography. The novel intermediates of Formula VII are solids.Structural assignments are confirmed by infrared and nuclear magneticresonance spectral analyses.

Step (6) is carried out be reacting the novel substituted4-chloro-6-heterocyclicaminopyrimidine of Formula VII with hydrazinehydrate. The reaction is facile and is generally carried out at moderatetemperatures, for example, from -20° C. to the reflux temperature of thesolvent. The reaction is generally carried out by adding two equivalentsof hydrazine hydrate to a solution of the pyrimidine. The solvent willgenerally be a lower alkanol. The solid product is separated byconventional methods such as filtration, extraction or chromatographyand is the same novel intermediate of Formula VIII obtained from step(4).

Step (7) is carried out by reacting the intermediate of Formula VIIIwith an orthoester of formula VIIIA. Such orthoesters are well known andreadily available. The suitable orthoesters include trimethylorthoformate, triethyl orthoformate, triethyl orthoacetate, triethylorthopropionate and the like. Since the orthoesters are liquids, it isconvenient to mix the intermediates of Formula VIII with an excess oforthoester and to heat the mixture at reflux until reaction is complete.Good yields of the desired novel compounds of Formula I which aresubstituted 1,2,4-triazolo[4,3-c]pyrimidines are isolated byconventional methods. When R₅ is hydrogen it is necessary to monitor thereaction as it proceeds, or rearrangement to the [1,5-c]isomer mayoccur. Monitoring is carried out by conventional methods such asthin-layer chromatography or nuclear magnetic resonance spectralanalysis. The structural assignments are made based on infrared andnuclear magnetic resonance spectral analyses. The products are generallywhite crystalline solids.

Scheme II shows a method for preparation of compounds of Formula Iwherein R₅ is ##STR8## wherein X is as defined previously; R₇ ishydrogen or lower alkyl; and R₃ and R₈ are as defined previously.##STR9##

Scheme II requires heating of the intermediate of Formula IX in anexcess of the heterocyclic amine of the formula VIA optionally in aninert solvent such as diglyme or dioxane. Intermediates of Formula IXare either known or may be prepared from known starting materials usingknown methods. The reaction is generally carried out at the refluxtemperature of the mixtures. The product is isolated by conventionalmethods such as filtration, extraction or chromatography. Chromatographyis preferred since the product is usually a mixture consisting of thedesired product of Formula I and of the triazolo[1,5-c]pyrimidine ofFormula X.

The following examples are provided to illustrate the methods used inthe invention. They are not intended to limit the invention.

EXAMPLE 1 Preparation of3,5-Diethyl-7-(4-methyl-1-piperazino)-1,2,4-triazolo[4,3-c]pyrimidineaccording to Scheme I, Steps (1), (2), (3), (4) and (7) Part A1.Preparation of Propionamidine

Hydrogen chloride gas was bubbled into a mixture of 110 g (2.00 mole) ofpropionitrile and 70.0 g (2.19 mole) of methanol while cooling with anice bath and maintaining the reaction mixture under a nitrogen streamuntil 78.5 g (2.15 mole) of hydrogen chloride had been added. Thereaction flask was stoppered and stirred at 20° C. for 4.5 days. To thismixture was added 150 ml of methanol. Ammonia gas was bubbled into themixture (accompanied by cooling) for two hours until the mixture wasbasic to litmus paper. The flask was stoppered and stirred for about 16hours. The solids were removed by filtration, washed with methanol, andthe washings and filtrate were concentrated by evaporation. The residuewas dissolved in 400 ml of ethanol. The solution was cooled and thenfiltered, and the filtrate was concentrated by evaporation. The residuewas again dissolved in ethanol, cooled, filtered and the filtrateevaporated to provide a residue which crystallized to provide 114 g(53%) of propionamidine hydrochloride.

Part A 2. Alternative Preparation of Propionamidine

A mixture of 35 g (0.2 mole) of triethyl orthopropionate and 15.4 g (0.2mole) of ammonium acetate was reacted as described by Taylor, et. al.,J. Am. Chem. Soc., 1960, 82, 3138, by heating the mixture at reflux for45 minutes. The product was isolated by distilling off ethanol, followedby filtration to provide 17 g of propionamidine acetate, m.p. 165°-167°C. An additional 3 g was obtained by concentrating the filtrate andadding acetone to provide a 77% yield overall. The structure wasconfirmed by nuclear magnetic resonance and infrared spectral analyses.

Part B1. Preparation of 4,6-Dihydroxy-2-ethylpyrimidine according toStep (1)

To a cooled, stirred solution of 25% sodium methoxide (1200 ml, 5.55mole) was added a slurry of 200 g (1.85 mole) of propionamidehydrochloride in 300 ml of methanol. Next, 244 g (1.85 mole) of dimethylmalonate was added and the mixture was permitted to warm to about 20°C., after which it was stirred for 16 hours. The mixture was evaporatedin vacuo and water (about 2 l) was added. This mixture was neutralizedwith concentrated hydrochloric acid to provide a white precipitate whichwas separated by filtration to provide 230 g (96%) of4,6-dihydroxy-2-ethylpyrimidine, m.p. 312°-315° C. The structuralassignment was confirmed by infrared and nuclear magnetic resonancespectral analyses.

Part B2. Alternative Preparation of 4,6-Dihydroxy-2-ethylpyrimidine

Using the procedure of Example 1, Part B1, 18.5 g (0.14 mole) ofpropionamidine acetate and 90 ml of 25% sodium methoxide were reactedwith dimethyl malonate (0.14 mole) to provide 16.5 g (89.5%) of4,6-dihydroxy-2-ethylpyrimidine according to Step (1).

Part C. Preparation of 4,6-Dichloro-2-ethylpyrimidine

A mixture of 150 g (1.15 mole) of 4,6-dihydroxy-2-ethylpyrimidine and1073 g (7.0 mole, 640 ml) of phosphorus oxychloride was heated at refluxfor 6 hours, cooled and evaporated in vacuo to provide a brown oil asthe residue. The residue was poured into 1500 ml of an ice-watermixture. The mixture was extracted thrice with 400 ml portions ofdiethyl ether. The combined ether extracts were washed sequentially withwater (200 ml), 5% sodium hydroxide solution (twice with 200 mlportions), and saturated sodium chloride solution (200 ml), and werethen dried over magnesium sulfate. Evaporation of the ether provided anoil which was distilled to provide 41 g (70%) of4,6-dichloro-2-ethylpyrimidine, b.p. 55-60 C/1.5 to 4 mm Hg. Thestructural assignment was confirmed by infrared and nuclear magneticresonance spectral analyses.

Part D. Preparation of 4-Chloro-2-ethyl-6-hydrazinylpyrimidine accordingto Step (3)

To a stirred, cold (0° C.) solution of 60 g (0.34 mole) of4,6-dichloro-2-ethylpyrimidine in 500 ml of methanol was added 35 g (0.7mole) of hydrazine hydrate while maintaining the temperature below 10°C. Stirring was continued for 2 hours after completion of the addition,the temperature being maintained at 0° C. The mixture was allowed towarm to about 20° C. and was stirred for 16 hours. The white solid wascollected by filtration and the filtrate was partially evaporated toprovide a second crop. The combined solids were washed with water andair dried to provide 51 g (77%) of4-chloro-2-ethyl-6-hydrazinylpyrimidine, m.p. 147°-150° C.

Part E. Preparation of2-Ethyl-6-hydrazinyl-4-(4-methyl-1-piperazinyl)pyrimidine according toStep (4)

A mixture of 8.3 g (0.05 mole) of4-chloro-2-ethyl-6-hydrazinylpyrimidine and 11 g (0.10 mole) of1-methylpiperazine in 250 ml of water was heated at reflux for 16 hoursand was then cooled and extracted with chloroform. The extracts weredried over magnesium sulfate and were then evaporated to provide 8.3 g(70%) of 2-ethyl-6-hydrazinyl-4-(4-methyl-1-piperazinyl)pyrimidine.

Part F. Preparation of3,5-Diethyl-7-(4-methyl-1-piperazinyl)-1,2,4-triazolo[4,3-c]pyrimidineaccording to Step (7)

A mixture of 8.3 g (0.045 mole) of2-ethyl-6-hydrazinyl-4-(4-methyl-1-piperazinyl)pyrimidine and 75 ml oftriethyl orthopropionate was heated at reflux for 48 hours. Aftercooling the mixture was evaporated in vacuo. Diethyl ether was added tothe residue and the mixture was cooled. The precipitate was collected byfiltration to provide 4.5 g (37%) of3,5-diethyl-7-(4-methyl-1-piperazinyl)-1,2,4-triazolo[4,3-c]pyrimidine.Recrystallizations from ethyl acetate-hexane and ethylacetate-cyclohexane provided white crystalline product, m.p. 128°-131°C. Analysis for C₁₄ H₂₂ N₆ : Calculated: %C, 61.3; %H, 8.1; %N, 30.6;Found: %C, 59.8; %H, 8.2; %N, 30.1. The structural assignment wasconfirmed by nuclear magnetic resonance and infrared spectral analyses.

EXAMPLES 2-23

Using the method of Example 1, Part E, the indicated amines of FormulaVIA were reacted with the indicated known4-chloro-2-alkyl-6-hydrazinylpyrimidines of Formula VI to provide thenovel intermediates of Formula VIII (Table I).

                                      TABLE I                                     __________________________________________________________________________         Amine    Pyrimidine Intermediate           Melting Point                 Example                                                                            Intermediate                                                                           of Formula VI                                                                              Intermediate of Formula VIII                                                                       (in °C.)               __________________________________________________________________________          ##STR10##                                                                              ##STR11##                                                                                  ##STR12##           none taken (yield 66%)          3                                                                                 ##STR13##                                                                             "                                                                                           ##STR14##           158-160 (yield 94.5%)           4                                                                                 ##STR15##                                                                             "                                                                                           ##STR16##           129-133 (yield 75%)             5                                                                                 ##STR17##                                                                              ##STR18##                                                                                  ##STR19##           112-115                         6                                                                                 ##STR20##                                                                              ##STR21##                                                                                  ##STR22##           none taken (yield 84%)          7                                                                                 ##STR23##                                                                              ##STR24##                                                                                  ##STR25##           144-146 (yield 71%)             8                                                                                 ##STR26##                                                                              ##STR27##                                                                                  ##STR28##           none taken (yield 85%)          9                                                                                 ##STR29##                                                                              ##STR30##                                                                                  ##STR31##           none taken (yield 68%)           10                                                                               ##STR32##                                                                              ##STR33##                                                                                  ##STR34##           183-185                         11                                                                                ##STR35##                                                                              ##STR36##                                                                                  ##STR37##           none taken (yield 66%)          12                                                                                ##STR38##                                                                              ##STR39##                                                                                  ##STR40##           203-204                         13                                                                                ##STR41##                                                                              ##STR42##                                                                                  ##STR43##           174-177                         14                                                                                ##STR44##                                                                              ##STR45##                                                                                  ##STR46##           155-157                         15                                                                                ##STR47##                                                                              ##STR48##                                                                                  ##STR49##           147-149                         16                                                                                ##STR50##                                                                              ##STR51##                                                                                  ##STR52##           122-123                         17                                                                                ##STR53##                                                                              ##STR54##                                                                                  ##STR55##           124-126                         18                                                                                ##STR56##                                                                              ##STR57##                                                                                  ##STR58##           124-126                         19                                                                                ##STR59##                                                                              ##STR60##                                                                                  ##STR61##           none taken                      20                                                                                ##STR62##                                                                              ##STR63##                                                                                  ##STR64##           none taken                      21                                                                                ##STR65##                                                                              ##STR66##                                                                                  ##STR67##           (oil)                           22                                                                                ##STR68##                                                                              ##STR69##                                                                                  ##STR70##           (oil)                           23                                                                                ##STR71##                                                                              ##STR72##                                                                                  ##STR73##           140-143                       __________________________________________________________________________

EXAMPLES 24-67

Using the method of Part F, Example 1, the indicated intermediates ofFormula VIII were reacted with the indicated trialkyl orthoesters toprovide the indicated compounds of Formula I (Table II).

                                      TABLE II                                    __________________________________________________________________________       Intermediate                                  Calculated: % C; % H; %                                                       N                            Ex.                                                                              of Formula VIII         Product of Formula IX Found: % C; % H; % N         No.                                                                              R.sub.5                                                                              R.sub.8                                                                           X   Ortho Ester                                                                            R.sub.3                                                                              R.sub.5                                                                              R.sub.8                                                                           X   (m.p. in                     __________________________________________________________________________                                                     °C.)                  24 CH.sub.3                                                                             H   SO.sub.2                                                                          triethyl H      CH.sub.3                                                                             H   SO.sub.2                                                                          44.9; 4.9; 26.2                                orthoformate                   44.9; 4.9; 26.3                                                               (299-300)                    25 CH.sub.3                                                                             H   SO.sub.2                                                                          triethyl CH.sub.3                                                                             CH.sub.3                                                                             H   SO.sub.2                                                                          47.0; 5.4; 25.0                                orthoacetate                   47.1; 5.4; 24.9                                                               (307-308)                    26 CH.sub.2 CH.sub.2 CH.sub.3                                                           H   O   triethyl H      CH.sub.2 CH.sub.2 CH.sub.3                                                           H   O   58.3; 6.9; 28.3                                orthoformate                   58.2; 7.0; 28.4                                                               (200-202)                    27 CH.sub. 2 CH.sub.2 CH.sub.3                                                          H   O   triethyl CH.sub.2 CH.sub.3                                                                    CH.sub.2 CH.sub.2 CH.sub.3                                                           H   O   61.1; 7.7; 25.4                                orthopropionate                60.9; 7.9; 25.7                                                               (179-181)                    28 CH.sub.2 CH.sub.2 CH.sub.3                                                           H   S   triethyl H      CH.sub.2 CH.sub.2 CH.sub.3                                                           H   S   54.7; 6.5; 26.6                                orthoformate                   54.6; 6.5; 26.9                                                               (208-209)                    29 CH.sub.2 CH.sub.2 CH.sub.3                                                           H   S   triethyl CH.sub.2 CH.sub.3                                                                    CH.sub.2 CH.sub.2 CH.sub.3                                                           H   S   57.7; 7.3; 24.0                                orthopropionate                57.7; 7.5; 24.4                                                               (143-144)                    30 CH.sub.2 CH.sub.2 CH.sub.3                                                           H   CH.sub.2                                                                          triethyl CH.sub.2 CH.sub.3                                                                    CH.sub.2 CH.sub.2 CH.sub.3                                                           H   CH.sub.2                                                                          (as H.sub.2 SO.sub.4                                                          salt):                                         orthopropionate                48.5; 6.8; 18.9                                                               48.4; 7.0; 19.0                                                               (190-192)                    31 CH.sub.3                                                                             H   S   triethyl H      CH.sub.3                                                                             H   S   51.0; 5.6; 29.8                                orthoformate                   51.0; 5.5; 29.6                                                               (234-237)                    32 CH.sub.2 CH.sub.3                                                                    H   CH.sub.2                                                                          triethyl CH.sub.2 CH.sub.3                                                                    CH.sub.2 CH.sub.3                                                                    H   CH.sub.2                                                                          64.8; 8.2; 27.0                                orthopropionate                65.1; 8.3; 27.2                                                               (120-122)                    33 CH.sub.2 CH.sub.3                                                                    H   S   triethyl CH.sub.2 CH.sub.3                                                                    CH.sub.2 CH.sub.3                                                                    H   S   56.3; 6.9; 25.2                                orthopropionate                56.1; 7.2; 25.5                                                               (149-150)                    34 CH.sub.2 CH.sub.3                                                                    H   S   triethyl CH.sub.3                                                                             CH.sub.2 CH.sub.3                                                                    H   S   54.7; 6.5; 26.6                                orthoacetate                   54.4; 6.7; 26.7                                                               (168-170)                    35 CH.sub.2 CH.sub.3                                                                    H   S   triethyl H      CH.sub.2 CH.sub.3                                                                    H   S   53.0; 6.0; 28.1                                orthoformate                   52.6; 6.2; 28.2                                                               (243-245)                    36 CH.sub.2 CH.sub.3                                                                    H   O   triethyl CH.sub.3                                                                             CH.sub.2 CH.sub.3                                                                    H   O   58.3; 6.9; 28.3                                orthoacetate                   58.2; 7.0; 28.5                                                               (200-203)                    37 CH.sub.2 CH.sub.3                                                                    H   O   triethyl CH.sub.2 CH.sub.3                                                                    CH.sub.2 CH.sub.3                                                                    H   O   59.7; 7.3; 26.8                                orthopropionate                59.6; 7.4; 27.0                                                               (173-174)                    38 CH.sub.2 CH.sub.3                                                                    H   O   triethyl H      CH.sub.2 CH.sub.3                                                                    H   O   56.6; 6.5; 30.0                                orthoformate                   56.6; 6.4; 30.3                                                               (223-224)                    39 CH.sub.3                                                                             H   O   trimethyl                                                                              H      CH.sub.3                                                                             H   O   54.8; 6.0; 31.9                                orthoformate                   54.7; 6.0; 31.4                                                               (208-210)                    40 CH.sub.3                                                                             H   O   triethyl CH.sub.3                                                                             CH.sub.3                                                                             H   O   56.6; 6.5; 30.0                                orthoacetate                   56.7; 6.3; 30.3                                                               (171-173)                    41 CH.sub.3                                                                             H   O   triethyl CH.sub.2 CH.sub.3                                                                    CH.sub.3                                                                             H   O   58.3; 6.9; 28.3                                orthopropionate                57.9; 7.0; 28.3                                                               (169-172)                    42 CH.sub.3                                                                             H   S   triethyl CH.sub.3                                                                             CH.sub.3                                                                             H   S   53.0; 6.0; 28.1                                orthoacetate                   53.1; 6.3; 28.3                                                               (223-225)                    43 CH.sub.3                                                                             H   S   triethyl CH.sub.2 CH.sub.3                                                                    CH.sub.3                                                                             H   S   54.8; 6.5; 26.6                                orthopropionate                54.4; 6.7; 26.8                                                               (161-163)                    44 CH.sub.3                                                                             CH.sub.3                                                                          S   triethyl H      CH.sub.3                                                                             CH.sub.3                                                                          S   53.0; 6.0; 28.1                                orthoformate                   53.2; 6.3; 28.4                                                               (182-184)                    45 CH.sub.3                                                                             CH.sub.3                                                                          S   triethyl CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                          S   54.7; 6.5; 26.6                                orthoacetate                   54.4; 6.6; 26.9                                                               (184-185)                    46 CH.sub.3                                                                             CH.sub.3                                                                          S   triethyl CH.sub.2 CH.sub.3                                                                    CH.sub.3                                                                             CH.sub.3                                                                          S   56.3; 6.9; 25.2                                orthopropionate                56.4; 7.1; 25.1                                                               (129-130)                    47 CH.sub.3                                                                             CH.sub.3                                                                          SO.sub.2                                                                          triethyl H      CH.sub.3                                                                             CH.sub.3                                                                          SO.sub.2                                                                          46.9; 5.4; 24.9                                orthoformate                   47.0; 5.3; 25.2                                                               (234-236)                    48 CH.sub.2 CH.sub.3                                                                    H   S   trimethyl                                                                              CH.sub.2 CH.sub.2 CH.sub.3                                                           CH.sub.2 CH.sub.3                                                                    H   S   57.7; 7.3; 24.0                                orthobutyrate                  57.6; 7.5; 24.2                                                               (163-165)                    49 CH.sub.2 CH.sub.3                                                                    H   O   trimethyl                                                                              CH.sub.2 CH.sub.2 CH.sub.3                                                           CH.sub.2 CH.sub.3                                                                    H   O   61.1; 7.7; 25.4                                orthobutyrate                  61.0; 7.9; 25.8                                                               (164-166)                    50 CH.sub.2 CH.sub.3                                                                    H   O   trimethyl                                                                              CH(CH.sub.3).sub.2                                                                   CH.sub.2 CH.sub. 3                                                                   H   O   61.1; 7.7; 25.4                                orthoisobutyrate               61.0; 7.7; 25.3                                                               (136-137)                    51 CH.sub.2 CH.sub.3                                                                    H   S   trimethyl                                                                              CH(CH.sub.3).sub.2                                                                   CH.sub.2 CH.sub.3                                                                    H   S   57.7; 7.3; 24.0                                orthoisobutyrate               57.8; 7.3; 24.2                                                               (143-144)                    52 CH.sub.2 CH.sub.2 CH.sub.3                                                           H   S   trimethyl                                                                              CH.sub.2 CH.sub.2 CH.sub.3                                                           CH.sub.2 CH.sub.2 CH.sub.3                                                           H   S   59.0; 7.6; 22.9                                orthobutyrate                  59.0; 7.5; 23.1                                                               (134-135)                    53 CH.sub.2 CH.sub.2 CH.sub.3                                                           H   O   trimethyl                                                                              CH.sub.2 CH.sub.2 CH.sub.3                                                           CH.sub.2 CH.sub.2 CH.sub.3                                                           H   O   62.3; 8.0; 24.2                                orthobutyrate                  62.2; 8.1; 24.1                                                               (139-140)                    54 CH.sub.2 CH.sub.2 CH.sub.3                                                           H   S   trimethyl                                                                              CH(CH.sub.3).sub.2                                                                   CH.sub.2 CH.sub.2 CH.sub.3                                                           H   S   59.0; 7.6; 22.9                                orthoisobutyrate               59.1; 7.7; 23.0                                                               (134-136)                    55 CH.sub.2 CH.sub.2 CH.sub.3                                                           H   O   trimethyl                                                                              CH(CH.sub.3).sub.2                                                                   CH.sub.2 CH.sub.2 CH.sub.3                                                           H   O   62.3; 8.0; 24.2                                orthoisobutyrate               62.4; 8.1; 24.6                                                               (116-117)                    56 CH(CH.sub.3).sub.2                                                                   H   O   triethyl H      CH(CH.sub.3).sub.2                                                                   H   O   (as H.sub.2 SO.sub.4                                                          Salt):                                         orthoformate                   41.7; 5.5; 20.3                                                               41.6; 5.7; 20.6                                                               (177-178)                    57 CH(CH.sub.3).sub.2                                                                   H   O   triethyl CH.sub.2 CH.sub.3                                                                    CH(CH.sub.3).sub.2                                                                   H   O   (as H.sub.2 SO.sub.4                                                          Salt):                                         orthopropionate                45.0; 6.2; 18.8                                                               44.9; 6.3; 19.0                                                               (167-168)                    58 CH(CH.sub.3).sub.2                                                                   H   O   trimethyl                                                                              CH.sub.2 CH.sub.2 CH.sub.3                                                           CH(CH.sub.3).sub.2                                                                   H   O   (as H.sub.2 SO.sub.4                                                          Salt):                                         orthobutyrate                  46.5; 6.5; 18.1                                                               46.2; 6.5; 18.3                                                               (162-163)                    59 CH(CH.sub.3).sub.2                                                                   H   S   triethyl CH.sub.3                                                                             CH(CH.sub.3).sub.2                                                                   H   S   (as H.sub.2 SO.sub.4                                                          Salt):                                         orthoacetate                   41.6; 5.6; 18.7                                                               41.6; 5.8; 18.8                                                               (170-172)                    60 CH(CH.sub.3).sub.2                                                                   H   S   triethyl CH.sub.2 Ch.sub.3                                                                    CH(CH.sub.3).sub.2                                                                   H   S   (as H.sub.2 SO.sub.4                                                          Salt):                                         orthopropionate                43.2; 6.0; 18.0                                                               43.1; 6.1; 18.2                                                               (174-175)                    61 C.sub.6 H.sub.5                                                                      H   O   triethyl H      C.sub.6 H.sub.5                                                                      H   O   64.0; 5.4; 24.9                                orthoformate                   63.8; 5.2; 24.7                                                               (>280)                       62 H      H   S   trimethyl                                                                              H      H      H   S   48.8; 5.0; 31.7                                orthoformate                   48.2; 4.9; 31.3                                                               (177-179)                    63 H      H   NCH.sub.3                                                                         trimethyl                                                                              H      H      H   NCH.sub.3                                                                         55.0; 6.5; 38.5                                orthoformate                   54.9; 6.4; 38.1                                                               (167-170)                    64 CH.sub.3                                                                             H   NCH.sub.3                                                                         triethyl H      CH.sub.3                                                                             H   NCH.sub.3                                                                         56.9; 6.9; 36.2                                orthoformate                   56.8; 6.8; 36.6                                                               (177-179)                    65 (CH.sub.2).sub.2 CH.sub.3                                                            H   NCH.sub.3                                                                         triethyl CH.sub.2 CH.sub.3                                                                    (CH.sub.2).sub.2 CH.sub.3                                                            H   NCH.sub.3                                                                         62.5; 8.4; 29.1                                orthopropionate                61.9; 8.5; 29.3                                                               (126-129)                    66 H      H   S   triethyl CH.sub.2 CH.sub.3                                                                    H      H   S   53.0; 6.1; 28.1                                orthopropionate                53.1; 6.2; 28.1                                                               (125-127)                    67 (CH.sub.2).sub.2 CH.sub.3                                                            H   NCH.sub.3                                                                         triethyl H      (CH.sub.2).sub.2 CH.sub.3                                                            H   NCH.sub.3                                                                         60.0; 7.7; 32.2                                orthoformate                   59.5; 7.7; 32.0                                                               (162-163)                    __________________________________________________________________________

EXAMPLE 68 Part A Preparation of4-Chloro-2-methyl-6-(4-morpholino)pyrimidine by Scheme I, Step (5)

A solution of 5.00 g (31.7 mmole) of 4,6-dichloro-2-methylpyrimidine and6.00 g (68.9 mmole) of morpholine in 50 ml of water was heated on asteam cone for about 18 hours. The mixture was diluted with water andcooled. The white solid was separated by filtration, washed with waterand dried to provide 4.84 g (72%) of4-chloro-2-methyl-6-(4-morpholino)pyrimidine. The structural assignmentwas confirmed by infrared and nuclear magnetic resonance spectralanalyses.

Part B Preparation of 4-Hydrazino-2-methyl-6-(4-morpholino)pyrimidine byScheme I, Step (6)

To a mixture of 4.70 g (22 mmole) of4-chloro-2-methyl-6-(4-morpholino)pyrimidine in 50 ml of ethanol wasadded 2.2 g (44 mmole) of hydrazine hydrate and the mixture was heatedat its reflux temperature for 16 hours. Cooling provided a precipitatewhich was separated by filtration and washed with ethanol to provide3.15 g (68%) of white solid4-hydrazino-2-methyl-6-(4-morpholino)-pyrimidine. The structuralassignment of the product was confirmed by infrared and nuclear magneticresonance spectral analyses and comparison with the same compound madein Example 9.

EXAMPLES 69-71

Using the method of Part A, Example 68, the indicated intermediate ofFormula V was reacted with the indicated amine of Formula VIA to providethe indicated intermediate of Formula VII (Table III).

                                      TABLE III                                   __________________________________________________________________________    Example                                                                            Intermediate                                                                             Heterocyclic Amine                                                                      Intermediate                                        Number                                                                             of Formula V                                                                             of Formula VIA                                                                          of Formula VII                                      __________________________________________________________________________      69                                                                                ##STR74##                                                                                ##STR75##                                                                               ##STR76##                                                                    m.p. 147.5-150° C., White Solid                70                                                                                ##STR77##                                                                                ##STR78##                                                                               ##STR79##                                                                    m.p. 210-220° C., White Solid                  71                                                                                ##STR80##                                                                                ##STR81##                                                                               ##STR82##                                                                    m.p. about 200° C.                           __________________________________________________________________________

EXAMPLES 72-74

Using the method of Part B, Example 68, the indicated intermediate ofFormula VII was reacted with hydrazine hydrate to provide the indicatedintermediate of Formula VIII (Table IV).

                                      TABLE IV                                    __________________________________________________________________________         Intermediate                                                                          Intermediate                                                     Example                                                                            of Formula VII                                                                        of Formula VIII                                                  __________________________________________________________________________      72 Example 69                                                                             ##STR83##        white solid                                      73 Example 70                                                                             ##STR84##        m.p. 232-234° C.; white solid             74 Example 71                                                                             ##STR85##        m.p. 250-253° C.; white                 __________________________________________________________________________                                   solid                                      

EXAMPLES 75-78

Additional intermediates of Formula VII which may be prepared startingwith intermediates of Formula V and using the method of Example 68, PartA, are described in Table V.

                  TABLE V                                                         ______________________________________                                        Intermediate                                                                              Heterocyclic Amine                                                                          Intermediate                                        of Formula III                                                                            of Formula VIA                                                                              of Formula VII                                      ______________________________________                                        4,6-dichloro-2-ethyl-                                                                     thiomorpholine                                                                              4-chloro-2-ethyl-6-(4-                              pyrimidine                thiomorpholino)-                                                              pyrimidine                                          4,6-dichloro-2-(n-                                                                        piperidine    4-chloro-6-(1-                                      propyl)-pyrimidine        piperidinyl)-2-(n-                                                            propyl)pyrimidine                                   4,6-dichloro-2,5-                                                                         piperazine    4-chloro-2,5-dimethyl-                              dimethylpyrimidine        6-(1-piperazinyl)                                                             pyrimidine                                          4,6-dichloro-2-                                                                           N-methyl-     4-chloro-2-isobutyl-6-                              isobutylpyrimidine                                                                        piperazine    (4-methyl-1-piper-                                                            azinyl)pyrimidine                                   ______________________________________                                    

EXAMPLE 79 Preparation According to Scheme I of5-methylthio-7-(4-morpholino)-1,2,4-triazolo[4,3-c]pyrimidine Part APreparation of 4-Hydrazinyl-2-methylthio-6-(4-morpholino)pyrimidineaccording to Scheme I, Step (4)

To a solution of 3.0 g (15.7 mmole) of4-chloro-6-hydrazinyl-2-methylthiopyrimidine in 50 ml of water was added2.8 g (32.2 mmole) of morpholine, and the mixture was heated at refluxfor two days. Cooling gave a precipitate which was separated byfiltration, washed with water and dried to provide off-white solid4-hydrazinyl-2-methylthio-6-(4-morpholino)pyrimidine, m.p. 134°-144° C.The structural assignment was confirmed by infrared and nuclear magneticresonance spectral analyses.

Part B Preparation of5-Methylthio-7-(4-morpholino)-1,2,4-triazolo[4,3-c]pyrimidine accordingto Scheme I, Step (7)

A mixture of 24.75 g (103 mmole) of4-hydrazinyl-2-methylthio-6-(4-morpholino)pyrimidine and 200 ml oftriethyl orthoformate was heated at 120° C. in an open flask for 60hours. The mixture was cooled, then diluted with 300 ml of diethylether. The precipitate was separated by filtration, washed with etherand dried to provide5-methylthio-7-(4-morpholino)-1,2,4-triazolo[4,3-c]-pyrimidine, m.p.212°-213° C. after two recrystallizations from chloroform-hexane.

EXAMPLES 80-82

Using the method of Example 79, Parts A and B, the intermediates ofFormula VIII and final compounds of Formula I shown in the followingtable were prepared from 4-chloro-6-hydrazino-2-methylthiopyrimidine andthe indicated amine of Formula VIA (Table VI). The structures of thecompounds of Formulas VIII and I shown in Table VI were confirmed byinfrared and nuclear magnetic resonance spectral analyses.

                                      TABLE V                                     __________________________________________________________________________         Amine                                                                    Example                                                                            Reaction Intermediate of    Compound                                     Number                                                                             Formula VIA                                                                            of Formula VIII    of Formula I                                 __________________________________________________________________________      80                                                                                ##STR86##                                                                              ##STR87##                                                                                        ##STR88##                                     81                                                                                ##STR89##                                                                              ##STR90##                                                                                        ##STR91##                                     82                                                                                ##STR92##                                                                              ##STR93##                                                                                        ##STR94##                                   __________________________________________________________________________

EXAMPLE 83 Preparation of7-Methyl-5-(1-piperazino)-1,2,4-triazolo[4,3-c]pyrimidine by Scheme II

A mixture of 6.00 g (33.3 mmole) of7-methyl-5-methylthio-1,2,4-triazolo[4,3-c]pyrimidine, 30.0 g (0.35mmole) of piperazine and 250 ml of dioxane was refluxed under nitrogenfor six days. The mixture was cooled and concentrated in vacuo. Theresidue obtained was dissolved in 150 ml of water, and the solution wasextracted four times with 150 ml portions of chloroform. The extractswere washed thrice with 150 ml portions of water and twice with 150 mlportions of sodium chloride solution, and were dried over magnesiumsulfate. Evaporation of the extracts provided a yellow solid which wastaken up in 150 ml of chloroform, filtered and chromatographed on a highpressure liquid chromatograph, eluting with methanol-ethyl acetate(1:1). Infrared and nuclear magnetic resonance spectral analyses showedfractions 2 and 3 to contain7-methyl-5-(1-piperazino)-1,2,4-triazolo[1,5-c]pyrimidine, m.p. 92°-95°C. Fraction 4 contained7-methyl-5-(1-piperazinyl)-1,2,4-triazolo[4,3-c]pyrimidine, m.p.136°-139° C. Analysis: Calculated for C₁₀ H₁₄ N₆ : %C, 55.0; %H, 6.5;%N, 38.5. Found: %C, 54.5; %H, 6.4; %N, 37.9.

EXAMPLE 84 Preparation of7-Methyl-5-(4-methyl-1-piperazino)-1,2,4-triazolo[4,3-c]pyrimidine

Using the method of Example 83,7-methyl-5-methylthio-1,2,4-triazolo-[4,3-c]pyrimidine was reacted with4-methylpiperazine to provide a mixture of7-methyl-5-(4-methyl-1-piperazino)-1,2,4-triazolo[4,3-c]-pyrimidine,m.p. 170°-171° C. (Analysis: Calculated for C₁₁ H₁₆ N₆ : %C, 56.9; %H,6.9; %N, 36.2; Found: %C, 57.0; %H, 6.9; %N, 35.9) and7-methyl-5-(4-methyl-1-piperazino)-1,2,4-triazolo[1,5-c]-pyrimidine,m.p. 95°-98° C. These compounds were separated by high pressure liquidchromatography using 5% methanol in ethyl acetate containing a smallamount of diethylamine.

EXAMPLE 85 Preparation of7-Methyl-5-(4-morpholino)-1,2,4-triazolo[4,3-c]pyrimidine

A mixture of 6.0 g (33 mmole) of7-methyl-5-methylthio-1,2,4-triazolo[4,3-c]pyrimidine and 15 ml ofmorpholine was heated at reflux for 19 hours, cooled and diluted withdiethyl ether and hexane. The solid product was separated by filtrationand chromatographed on florisil, eluting sequentially with benzene, 10%ethyl acetate in benzene, 50% ethyl acetate in benzene, and ethylacetate. Early fractions were recrystallized from a benzene-hexanemixture to provide7-methyl-5-(4-morpholino)-1,2,4-triazolo-[1,5-c]pyrimidine, m.p.113°-114° C. Later fractions were recrystallized from an ethylacetate-hexane mixture, accompanied with treatment with decolorizingcharcoal, to provide7-methyl-5-(4-morpholino)-1,2,4-triazolo[4,3-c]pyrimidine, m.p.209°-210° C. Analysis: Calculated for C₁₀ H₁₃ N₅ O: %C, 54.8; %H, 6.0;%N, 31.9; Found: %C, 55.1; %H, 5.9; %N, 31.8.

EXAMPLE 86 Preparation of3-Methyl-5-methylthio-8-phenyl-7-(4-thiomorpholino)-1,2,4-triazolo-[4,3-c]pyrimidineaccording to Scheme II Part A Preparation of4-Chloro-2-methylthio-5-phenyl-6-(4-thiomorpholino)pyrimidine

A mixture of 25 g (0.093 mole) of4,6-dichloro-2-methylthio-5-phenylpyrimidine and 20 g (0.19 mole) ofthiomorpholine in 100 ml of methanol was stirred for 16 hours. The solidwas separated by filtration and dried to provide white crystals of crude4-chloro-2-methylthio-5-phenyl-6-(4-thiomorpholino)pyrimidine, m.p.110°-125° C.

Part B Preparation of4-Hydrazino-2-methylthio-5-phenyl-6-(4-thiomorpholino)pyrimidine

A mixture of 29 g (0.086 mole) of4-chloro-2-methylthio-5-phenyl-6-(4-thiomorpholino)-pyrimidine and 10.0g (0.2 mole) of hydrazine hydrate in 200 ml of ethanol was heated at itsreflux temperature for 70 hours. The mixture was cooled and the productwas separated by filtration. The product was white crystals of4-hydrazino-2-methylthio-5-phenyl-6-(4-thiomorpholino)pyrimidine, m.p.170°-171° C. The structure was confirmed by infrared and nuclearmagnetic resonance spectral analyses.

Part C Preparation of3-Methyl-5-methylthio-8-phenyl-7-(4-thiomorpholino)-1,2,4-triazolo[4,3-c]-pyrimidine

A mixture of 4.2 g (0.012 mole) of4-hydrazino-2-methylthio-5-phenyl-6-(4-thiomorpholino)-pyrimidine and 40ml of triethyl orthoacetate was heated at its reflux temperature forabout 64 hours, and was then allowed to cool. The solid precipitate wascollected by filtration, washed with hexane and dried. Recrystallizationfrom ethyl acetate provided 3.0 g of pale green crystals of3-methyl-5-methylthio-8-phenyl-7-(4-thiomorpholino)-1,2,4-triazolo[4,3-c]pyrimidine,m.p. 171°-172° C. This solid was dissolved in 40 ml of hot ethanol andan equimolar amount of sulfuric acid was added. The mixture was cooledand diethyl ether was added to precipitate yellow crystals of3-methyl-5-methylthio-8-phenyl-7-(4-thiomorpholino)-1,2,4-triazolo[4,3-c]pyrimidinedihydrogen sulfate, m.p. 193°-195° C. The salt was neutralized withammonium hydroxide to reprecipitate the free base which was againrecrystallized from ethyl acetate. Analysis: Calculated for C₁₇ H₁₉ N₅S₂ : %C, 57.1; %H, 5.4; %N, 19.6; Found: %C, 56.5; %H, 5.4; %N, 19.7.

EXAMPLE 87 Preparation of3-ethyl-5-methylthio-8-phenyl-7-(4-thiomorpholino)-1,2,4-triazolo[4,3-c]pyrimidine.

Using the method of Example 86, part C, the intermediate of Example 86,part B, was reacted with triethyl orthopropionate to provide3-ethyl-5-methylthio-8-phenyl-7-(4-thiomorpholino)-1,2,4-triazolo[4,3-c]pyrimidinedihydrogen sulfate, m.p. 205°-207° C. Analysis: Calculated for C₁₈ H₂₁N₅ S₂.H₂ SO₄ : %C, 46.0; %H, 4.9; %N, 14.9; Found: %C, 45.9; %H, 5.1;%N, 14.9. The crude free base had a melting point of 152°-155° C.

What is claimed is:
 1. A compound of the formula: ##STR95## wherein R₃is hydrogen or lower alkyl; one of R₅ and R₇ is the heterocyclicsubstituent ##STR96## wherein X is oxygen, sulfur, sulfinyl, sulfonyl,methylene, imido or N-lower alkylimido; when R₅ is said heterocyclicsubstituent, R₇ is hydrogen or lower alkyl; when R₇ is said heterocyclicsubstituent, R₅ is hydrogen, lower alkylthio, phenyl or lower alkyl; andR₈ is hydrogen, phenyl or lower alkyl; or a pharmaceutically acceptablesalt thereof.
 2. A compound according to claim 1, wherein X is sulfur oroxygen.
 3. A compound according to claim 2 wherein R₈ is hydrogen.
 4. Acompound according to claim 1, selected from the group consistingof:3,5-bis(n-propyl)-7-(4-thiomorpholino)-1,2,4-triazolo[4,3-c]-pyrimidine,5-ethyl-3-methyl-7-(4-thiomorpholino)-1,2,4-triazolo[4,3-c]-pyrimidine,3-methyl-5-methylthio-8-phenyl-7-(4-thiomorpholino)-1,2,4-triazolo[4,3-c]pyrimidine,5-ethyl-3-isopropyl-7-(4-thiomorpholino)-1,2,4-triazolo-[4,3-c]pyrimidine,3-ethyl-5-methyl-7-(4-thiomorpholino)-1,2,4-triazolo[4,3-c]-pyrimidine,3,5-bis(n-propyl)-7-(4-morpholino)-1,2,4-triazolo[4,3-c]-pyrimidine,3,5-diethyl-7-(1-piperidino)-1,2,4-triazolo[4,3-c]-pyrimidine,3-isopropyl-7-(4-morpholino)-5-n-propyl-1,2,4-triazolo[4,3-c]pyrimidine,7-(4-morpholino)-5-methylthio-1,2,4-triazolo[4,3-c]-pyrimidine,3-ethyl-5-n-propyl-7-(4-thiomorpholino)-1,2,4-triazolo-[4,3-c]pyrimidine,7-(4-methyl-1-piperazino)-5-(n-propyl)-1,2,4-triazolo[4,3-c]-pyrimidine,5-n-propyl-7-(4-thiomorpholino)-1,2,4-triazolo[4,3-c]-pyrimidine,5-ethyl-7-(4-morpholino)-1,2,4-triazolo[4,3-c]pyrimidine,5-ethyl-2-methyl-7-(4-morpholino)-1,2,4-triazolo[4,3-c]-pyrimidine, and3,5-diethyl-7-(4-thiomorpholino)-1,2,4-triazolo[4,3-c]-pyrimidine.
 5. Apharmaceutical composition comprising an effective amount of a compoundaccording to claim 1 and a pharmaceutically acceptable vehicle.
 6. Amethod for obtaining bronchodilation in a mammal, comprisingadministering an effective amount of a compound according to claim 1 tosaid mammal.
 7. A method according to claim 6, wherein said compound isadministered orally.